Vitamin D has been investigated as a potential preventive therapy for prostate cancer (CaP) because of its many anti-cancer activities. We demonstrate in the transgenic adenocarcinoma of mouse prostate (TRAMP) model of CaP that early treatment with 1,25(OH)2D3 prevents hormone responsive CaP and is associated with decreased proliferation and increased differentiation. The in vivo response of TRAMP prostate to 1,25(OH)2D3 treatment indicates a decrease in cell cycle modulators that regulate G2/M transition and n increase in E- Cadherin, a marker of differentiation. We have identified a novel interaction of VDR with a novel corepressor complex. We propose a model in which VDR corepressor increases during prostate cancer progression and in castration recurrent disease, resulting in repression of VDR mediated gene transcription. The biological consequence of these changes is a loss of vitamin D's anti-cancer activity. Therefore, the effectiveness of 1,25(OH)2D3 can be enhanced by inhibiting the corepressor. In Aim I we determine the molecular mediators of 1,25(OH)2D3 chemopreventive activity in vivo. In Aim II we determine the molecular mechanism of deregulated VDR-mediated transcription in CaP cells that escape 1,25(OH)2D3's chemopreventive activity by examine the function of a newly identified VDR corepressor. This project is innovative in the use of a transgenic model to define the mechanism of action of vitamin D's chemopreventive action in vivo. In this proposal we examine in detail VDR interaction with a newly identified VDR corepressor complex and the impact on vitamin D growth inhibition and gene transcription. We test whether inhibition of the corepressor activity improves the chemopreventive activity of 1,25(OH)2D3 in vivo for hormone responsive and castration recurrent CaP. Thus, these studies provide valuable preclinical data making this project translational in nature. The rationale for these studies is that an understanding of the mechanism of action of vitamin D chemopreventive activity at the molecular level provides the basis for developing improved therapeutics and identifying patients most/least likely to benefit from vitamin D therapy. PUBLIC HEALTH RELEVANCE: The progressive nature of the natural history of prostate cancer in combination with the long latency period, late onset and prevalence of the disease make prostate cancer a prime target for preventive strategies. The results from these studies will increase our understanding of the chemopreventive effects of vitamin D on differentiation and proliferation, identify changes in the expression of VDR interacting proteins that alters vitamin D response of the cell, and test a combinational therapy designed to improve the effectiveness of vitamin D's chemopreventive activity. Thereby, identifying molecular changes in the VDR signaling axis that may be used to identify men who would benefit the most or least from vitamin D therapy, identify new therapeutic targets for prevention and treatment of prostate cancer and ultimately impacting diagnosis, treatment and management prostate cancer.